1. Field of the Invention
This invention relates to a breath monitoring apparatus for diagnostic purposes and more particularly relates to a miniature spectroscopic gas analyzer for patient breath analysis to determine cardiac output (Q).
2. Background Information
The determination of Qxe2x80x94the amount of blood pumped by the heart per minutexe2x80x94at rest or during exercise is a powerful diagnostic tool for assessing patient health. Currently, the state of diagnostic technology is hospital and research-center based and features expensive, sensitive equipment.
A series of invasive and non-invasive techniques have been developed for Q monitoring during rest and submaximal exercise. The xe2x80x9cgoldxe2x80x9d standard generally is considered to be the dye-dilution method, with thermodilution a close second. Both methods are invasive and measure Q directly. Noninvasive techniques for Q monitoring encompass four principal approaches: 1) foreign gas rebreathing (e.g., acetylene or nitrous oxide analysis in breath), 2) indirect Fick (e.g., carbon dioxide analysis in breath), 3) transthoracic electrical bioimpedance, and 4) esophageal continuous-wave Doppler ultrasonography. These prior art methods are described below, along with their strengths and weaknesses.
Thermodilution (TD) is the traditional method for continuous and semicontinuous Q determination and many publications describe such a method. (Zollner, C. et al, Crit. Care Med. 1999, 27, 293-298; and Zollner, C. et al, J. Cardiothorac. Vasc. Anesth. 2000, 14, 125-129.) Also, numerous patents describing TD apparatus and accessories have been issued. Patents issued include U.S. Pat. No. 4,217,910, issued Aug. 19, 1980 to Khalil, H. H. for Internal jugular and left ventricular thermodilution catheter; U.S. Pat. No. 4,236,527, issued Dec. 2, 1980 to Newbower, R. S. et al for a Q detection by multiple frequency thermodilution and U.S. Pat. No. 4,819,655, issued Apr. 11, 1989 to Webler, W. E. for an Injectateless thermal Q determination method and apparatus.
However, this technique has significant drawbacks, primarily resulting from its invasive nature. A catheter needs to be inserted into the pulmonary artery and manual injection of fluid into the blood typically is required. Due to the serious nature of these interventions, the technique is usually restricted to monitoring hospitalized critically ill patients. Additionally, the response time of thermodilution monitors is too slow for the immediate detection of acute changes in Q and some clinical conditions, such as the rapid infusion of cold solutions, can interfere with the continuous Q measurement (Haller, M.; Zollner, C.; Briegel, J.; Forst, H., Crit. Care Med. 1995, 23, 860-866).
Non-Invasive methods of measuring Q include: Transthoracic electrical bioimpedance (TEB) monitors are non-invasive alternatives to TD but require the use of an endotracheal tube, which limits the technique""s practicality. (Vohra, A. et al, Br. J. Anaesth. 1991, 67, 64-68; Tibballs, J. et al, Anaesth. Intensive Care 1992, 20, 326-331; and Wallace, A. W. et al, Anesthesiology 2000, 92, 178-189). A number of patents describing the TEB technique have been issued (e.g., U.S. Pat. No. 5,423,326, issued Jun. 13, 1995, to Wang, X. et al, for an Apparatus and method for measuring Q and U.S. Pat. No. 5,469,859, issued Nov. 28, 1995 to Tsoglin, A. et al for a Non-invasive method and device for collecting measurements representing body activity and determining cardiorespiratory parameters of the human body based upon the measurements collected.).
Esophageal continuous-wave Doppler ultrasonography (ECO) has also emerged as a non-invasive method for Q monitoring (Pierpont, G. L. et al, J. Cardiovasc. Technol. 1990, 9, 31-34; Schiller, N. B., Anesthesiology 1991, 74, 9-14; and Webster, J. H. H. et al, European Journal of Vascular Surgery 1992, 6, 467-470). ECO has the advantage of being a non-invasive technique and has been recommended over thoracic electrical bio-impedance and thermo-dilution for field monitoring of seriously injured soldiers. (World, M. J. QJM-Mon. J. Assoc. Physicians 1996, 89, 457-462)
A number of Q monitors using the ECO technique have been patented. (e.g., U.S. Pat. No. 4,676,253, issued Jun. 30, 1987 to Baudino, M. D. for a Q monitor; U.S. Pat. No. 4,676,253, issued Jun. 30, 1987, to Newman, W. et al, for a Method and apparatus for non-invasive determination of Q; and U.S. Pat. No. 4,671,295, issued 1987, to Abrams, J. H. et al, for a Method for measuring Q.
A serious limitation of both the TEB and ECO methods is their inability to be employed during exercise due to excessive noise. A method of monitoring Q by computing blood pressure waveforms with fuzzy logic algorithms has also been disclosed recently, but has not been shown to be reliable or accurate especially when the subject is exercising. (U.S. Pat. No. 6,007,491, issued Dec. 28, 1999 to Ling, J. et al, for a Q monitor using fuzzy logic blood pressure analysis.)
Metabolic monitors commonly have been used to measure oxygen (O2) consumption and/or carbon dioxide (CO2) production to subsequently calculate Q. Such monitors are described by Zenger, M. R. et al, Am. J. Cardiol. 1993, 71, 105-109; Sasse, S. A. et al, Crit. Care Med. 1994, 22, 86-95; and Wippermann, C. F. et al, Intensive Care Med. 1996, 22, 467-471. Some of these devices have been patented (e.g., U.S. Pat. No. 5,836,300, issued Nov. 17, 1998; to Mault, J. R. for a Metabolic gas exchange and non-invasive Q monitor; and U.S. Pat. No. 5,971,934, issued Oct. 26, 1999 to Scherer, P. W. et al for a Non-invasive method for determining Q). However, the CO2 re-breathing method relies on a number of tenuous assumptions and is difficult to use during heavy exercise.
Non-invasive diagnostic methods for measuring Q using soluble gas uptake by the lungs also have existed for many years. Acetylene (C2H2) has been useful in such techniques, because its appropriate blood to gas partition coefficient usually lies in the range of 0.7-0.9 and is generally the preferred method for non-invasive Q monitoring. (Kennedy, R. R. et al Br. J. Anaesth. 1993, 71, 398-402 and Rosenthal, M. et al, Eur. Resp. J. 1997, 10, 2586-2590). C2H2-helium re-breathing techniques are based on the principle that C2H2, but not helium (He), diffuses from the alveoli to the pulmonary capillaries so that the rate of C2H2 decrease in the alveolar space depends on pulmonary blood flow. The traditional approach has been to measure C2H2 uptake during rebreathing from a closed system (Kallay, M. C. et al, Circulation 1985, 72, 188-188 and Crapo, R. O. et al, Am. Rev. Respir. Dis. 1986, 133, A65-A65.) However a non-rebreathing open-circuit steady-state method has also been reported. (Barker, R. C. et al, J. Appl. Physiol. 1999, 87, 1506-1512)
Both require rapid gas analyzers, especially if measurements are to be made at high breathing frequencies during exercise. An insoluble gas, such as He or sulfur hexafluoride (SF6) is required to determine the gas volume in the system and also as an indication when gas mixing is achieved. Carbon dioxide concentrations are also needed to convert measured minute ventilation to alveolar ventilation. It is alveolar and not minute ventilation that is used in the formula to determine Q.
The current instrument of choice for measuring C2H2 in breath is the respiratory mass spectrometer (MS). A sample is channeled from the breathing apparatus and introduced into the MS, where it is ionized and detected on a semi-continuous basis. Although this technique is reasonably fast (response times down to 20 msec., but typically 50 msec.), it does have some inherent limitations, including:
a.) Primarily a lab instrument,
b.) High power consumption,
c.) Bulky,
d.) High sensitivity to mechanical vibration and shock,
e.) Complex to use,
f.) Expensive to buy and maintain.
Faster response times are also important as the C2H2 concentration profile within a single breath is of interest. A portable, robust, non-invasive, low cost alternative to mass spectrometry measuring C2H2, CO2, and SF6 (or He) with very fast response times thus would be desirable. Portable infrared (IR) spectrometers have been used to monitor C2H2 but the performance of these instruments is questionable (possibly due to poor control of the sample cell environment and water interferences) and a MS is still required to measure the tracer gas, which is usually He. (Barazanji, K. W. et al, J. Appl. Physiol. 1996, 80, 1258-1262); Additionally, these IR analyzers are very slow (response time 200-300 msec.) and are single gas analyzers (i.e., one unit for each monitored gas, usually CO, CH4, and C2H2). Hence, metabolic carts equipped with an optional C2H2 analyzer are not generally effective technically, practically (bulky and intended for lab use only), or economically.
Clemensen et al. employed a multicomponent (O2, CO2, chlorodifluoromethane, and SF6) photoacoustic infrared and paramagnetic (IR/PM) gas analyzer in inert gas-rebreathing and metabolic gas exchange measurements. (Clemensen, P. et al, J. Appl. Physiol. 1994, 76, 2832-2839) The feasibility of replacing a conventional MS by such an instrument in a variety of non-invasive pulmonary gas exchange measurements was investigated for 10 subjects at rest and during submaximal exercise. The IR/PM showed promise, although further modifications to the instrument appeared to be required. This is the only report on the use of a spectroscopic gas analyzer measuring CO2, SF6, and a soluble gas, chlorodifluoromethane (freon 22). However, the system has important practical drawbacks, including cost and very slow response times (250 msec.).
It is one object of the present invention to provide a non-invasive, miniature breath monitoring and analysis device based on the measurement of a plurality of analytes via absorption spectroscopy.
Yet another object of the present invention is to provide a non-invasive breath monitoring and analysis device for measuring Q based on the measurement of acetylene (C2H2), carbon dioxide (CO2), sulfur hexafluoride (SF6), and water (H2O) via IR absorption spectroscopy.
Still another object of the present invention is to provide a non-invasive, breath monitoring analysis device where one or more gases are replaced by suitable alternatives (e.g., CO or N2O instead of C2H2, CH4 instead of SF6).
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring and analysis device that uses existing re-breathing and non-re-breathing protocols and data treatment.
Yet another object of the present invention is to provide a non-invasive, breath monitoring device that can be used with the subject at rest or under exercise; and can be used even under very heavy exercise.
Yet another object of the present invention is to provide a non-invasive, miniature breath monitoring device with an optional oxygen (O2) measurement.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that is low in cost to manufacture, rugged, portable, compact, low-power consumption, easy to maintain, allowing rapid transition from the laboratory to commercialization compared to the re-breathing mass spectrometer.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that does not need liquid nitrogen (LN2) cooling.
Yet another object of the present invention is to provide a breath monitoring analysis device for diagnostic purposes that has physical characteristics that allow the device to be used in the field.
Yet another object of the present invention is to provide a miniature breath monitoring and analysis device that allows data collected to be retrieved remotely by telemetry.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring analysis device that has fast response time of less than about 50 msec.
Another important object of the present invention is to provide a non-invasive, breath monitoring analysis device that uses low sampling volumes to keep the device compact and portable and with a fast response time.
Yet another object of the present invention is to provide a non-invasive, breath monitoring analysis device that includes a plurality of dedicated detectorsxe2x80x94at least one per analytexe2x80x94to monitor each compound of interest.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that allows analysis to be carried out in parallel, and measures the contents of a single optical sample cell.
Yet another object of the present invention is to provide a non-invasive, breath monitoring device that has a 100% duty cycle without the need for rotating filter wheels, or multiple sensors analyzing the contents of multiple sample cells.
Yet another object of the present invention is to provide a non-invasive breath monitoring device that utilizes one central processing unit (CPU) to manage all measurements.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that utilizes stackable, compact electronics.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that uses one or more fast response time detectors measuring SF6 or other gases, in the far-IR (i.e., xcex greater than 5.5 xcexcm) without the need for LN2 cooling.
Yet another object of the present invention is to provide a non-invasive, miniature breath monitoring device that removes spectral interference by using a gas cell filled with a high-optical depth of water vapor or any other spectral interferents in-line with the sample cell.
Still another object of the present invention is to provide a non-invasive, miniature monitoring device that utilizes an innovative, compact, modular optical design employing a plurality of beamsplitters for any combination of between 3 to 7 measurement channels.
Yet another object of the present invention is to provide a non-invasive breath monitoring device that uses optical fibers to guide the radiation to the measurement channels in lieu of multiple beamsplitters.
Yet another object of the present invention is to provide a non-invasive, miniature breath monitoring device that utilizes sequentially-pulse, multiple sources (e.g., TDL, LED, pulsed incandescent) coupled by optical fibers and one measurement detector.
Yet another object of the present invention is to provide a non-invasive, miniature breath monitoring device in which one embodiment allows for in-situ monitoring directly at the mouthpiece.
Still another object of the present invention is to provide a non-invasive, miniature breath monitoring device that can be easily adapted to monitor a wide range of gases relevant to Q monitoring and other medical applications of breath analysis by replacement of optical filters or sample cells.
The purpose of the present invention is to provide a non-invasive, miniature breath monitoring device or system that can be used as an effective medical diagnostic tool. The non-invasive, miniature breath monitoring device system disclosed herein utilizes an analyzer that is unique by virtue of a simultaneous and continuous measurement of C2H2, CO2, and SF6 in a gaseous matrix in one low-cost, miniature device approximately the size of a shoe box. The analyzer response is linear over full-scale ranges of 1.0-2.0%v for C2H2 and SF6; 10%v for CO2. A full-scale reading of 20% O2 is an optional add-on feature. The analyzer detection limits (2"sgr") are 2% of full-scale, or better, with a 10-50 msec. response time (10-90%); accuracy is typically xc2x12% of full-scale, or better. The rapid response time of the analyzer also distinguishes it from other gas analyzes used in the art. Unlike other IR C2H2 monitors, it does not suffer from cross-interferences, notably from H2O vapor. The instrument has a low sample volume (preferably less than 1.25 mL) and requires low power input (less than 50 watts during warm up, less than 25 watts during steady state). It is suitable for telemetry and is rugged with very low maintenance requirements.
The miniature breath monitoring device disclosed herein can be used in conjunction with the C2H2 foreign gas method to determine Q, by the re-breathing and non-rebreathing techniques. The latter is relatively new approach to Q monitoring, which is attractive in exercise studies, especially at altitude, as it avoids unpleasant re-breathing and resulting changes in alveolar PO2 or PCO2 as described in J. Appl. Physiol 1999, 87, 1506-1512 by Barker, R. C. et al.
Because of its compact, miniaturized size, the Q monitoring technology has a number of applications. It can be applied to monitoring hospitalized patients in critical and intensive care as well as in birthing rooms, screening of undeserved civilian communities, particularly in remote locations; rehabilitation exercise programs particularly following surgery; ambulance diagnostics; sports medicine and exercise physiology; screening of soldiers and potentially allowing a number of injured soldiers to be assessed rapidly; high altitude medical research; sustained micro-gravity research; and in animal studies particularly for dogs and horses.
Breath analysis as a non-invasive means of medical diagnostics has been touted for many years but the evolution of suitable instruments has been slow. U.S. Pat. No. 3,951,607 issued Apr. 20, 1976 to Fraser, R. B. for a gas analyzer discloses a chamber for measuring a number of breath components by mass spectrometry. The present invention is not limited in its usefulness to Q monitoring. Other applications include but are not limited to medical diagnostics by breath analysis of the following compounds:
a) carbon monoxide (CO) and a suitable inert reference gas (e.g., SF6 or CH4) for measuring lung volume and diffusing capacity and for evaluation of carboxyhemoglobin. In premature infant breath infected with hyperbilirubinemia, or hemolytic disease, breath analysis can be used as an index by bilirubin production. Statistics on measurement data can help predict whether the neonate is likely to develop potentially dangerous jaundice or not,
b) Acetone (1-500 xcexcg Lxe2x88x921) for diabetes diagnosis,
c) Nitric oxide (NO) (0-100 ppb) for monitoring patients with pneumonia, COPD exacerbation, cystic fibrosis, undergoing CABG, cirrhosis and/or on intravenous nitroglycerin. Also, the therapeutic administration of NO is now common practice in an intensive care environment for catastrophic lung disease, but the NO concentration in exhaled breath is not commonly measured. An analyzer capable of measuring the NO levels in exhaled breath would be useful for controlling the administered levels as well as determining the relationship between the treated disorder and the appropriate NO concentration in inhaled air for therapeutic treatment,
d) Hydrogen peroxide for investigating lung oxidative damage,
e) Ammonia (NH3), possibly for monitoring liver disease and in metabolic studies (e.g., during exercise).
f) 12CO2/13CO2 for monitoring the administration of 13C-labeled substances, such as used in screening of patients for glucose utilization, pancreatic function, intestinal bacterial overgrowth, liver function, and H. pylori infections of the digestive tract. Non-invasive evaluation of the nutritional status and body composition in pediatric patients also can be achieved by monitoring exhaled 13CO2, following bolus administration of 13CO2,
g) Breath ethane as a biomarker of free radical-mediated lipid peroxidation following reperfusion of the ichemic liver,
h) Sulfur compounds for diagnosis of liver dysfunction,
i) Anesthetic administration, including nitrous oxide (N2O),
j) Toxics (e.g., volatile organic compounds, either speciated or total) for occupational exposure monitoring.
The principal purpose of the invention disclosed herein consists in the quantitative analysis of gas-phase components of breath and the subsequent determination of Q. This measurement is made non-invasively by using novel embodiments of spectroscopic gas sensing technology. The present invention is unique in its optical design and by virtue of the fact that high-speed IR spectrometers are employed to monitor multiple species to determine an accurate measurement of Q. The use of such an approach has not been reported previously to make Q measurements on subjects at rest or during exercise.
With minor adjustments, the instrument is capable of measuring alternative analytes that may be of interest for Q monitoring (e.g., methane and freon 22). The integration of an O2 measurement channel allows the metabolic measurements to be carried out in conjunction with Q monitoring.
Similarly, the instrument has the capability of measuring numerous other gases, such as NH3, CO, N2O, ethanol, acetone, aldehydes, etc. for other biomedical applications, as described above. Substitution of the standard four measurement channels (i e CO2, H2O, C2H2, and SF6) with any of the above does not necessitate any software modifications and only requires minor hardware modifications (i.e., substitution of the optical filters).
The three principal gases of interest to Q monitoring, C2H2, CO2, and SF6, all possess unique IR absorption signatures centered at different wavelengths, as shown by FIG. 1. The amount of absorption is directly proportional to gas concentration, as described by the Beer-Lambert law. (Banwell, C. N. Fundamentals of Molecular Spectroscopy; 3 ed.; McGraw-Hill: London, 1983) For monitoring Q, a subject typically breathes an atmosphere consisting of C2H2 (approximately 2%v), SF6 (approximately 2%v), and O2 (20-30%v), balance nitrogen. CO2 is also present in exhaled breath. Therefore, a spectrometer that isolates the spectral window corresponding to the absorption signature of the target gases allows them to be monitored non-invasively and continuously by measuring the amount of radiation passing through the sample. A commonly used approach, known as non-dispersive IR (NDIR) spectroscopy (Hanst, P. L.; Hanst, S. T. Gas Measurement in the Fundamental Infrared Region; Sigrist, M. W., Ed.; John Wiley and Sons: New York, Chichester, Brisbane, Toronto, Singapore, 1994; Vol. 127, pp 335-470), relies on narrow bandpass optical filters (NBOFs) to isolate the radiation used to probe the fluid. The wavelength of this radiation is chosen to match that of the analyte""s absorption band. While this technique has been widely-used for gas analysis, it has not been applied to Q monitoring in the manner disclosed here. (e.g., U.S. Pat. No. 3,837,744, issued Sep. 24, 1974 to Egan, D. W. et al for Spectrometers, and U.S. Pat. No. 4,632,563, issued Dec. 30, 1986 to Lord, H. C. for Stack Gas Analysis, and U.S. Pat. No. 5,210,702, issued May 11, 1993 to Bishop, G. et al for Apparatus for Remote Analysis of Vehicle Emissions.)
The analyzer of the present invention uses a collimated beam of infrared (IR) radiation projected through a miniature sample cell. The radiation is subsequently analyzed by one or more spectrometers. The extent of signal attenuation as a function of radiation wavelength affords a direct measure of gas concentration and, hence, Q. The instrument uses small (e.g., diameter 12.5 mm) optics and low sample volumes (approximately 1.25 mL) leading to its miniature design.
The IR spectrometers in the analyzer sample at high frequencies (e.g., 2 KHz), yielding valuable Q information within a single breath. Measurements are preferably made in parallel and are automatically synchronized in the electronics. The instrument is calibrated using small samples of certified gas mixtures and is zeroed prior to each Q measurement. The breath analysis monitor is highly stable and insensitive to spectral interferences requiring no reference detector, although one may be included in certain embodiments of the invention.
The signals at the IR spectrometers, in the form of digital counts, are output to a storage device in the analyzer. These are converted to concentration readings and, hence, Q in real-time or by post-processing. Data is accessed/transmitted remotely by a radio modem, making the device useful in field telemetry applications.
The above and other objects, advantages, and novel features of the invention will be more fully understood from the following detailed description and the accompanying drawings, in which: